The Zebrafish <em>moonshine</em> Gene Encodes Transcriptional Intermediary Factor 1γ, an Essential Regulator of Hematopoiesis

<div><p>Hematopoiesis is precisely orchestrated by lineage-specific DNA-binding proteins that regulate transcription in concert with coactivators and corepressors. Mutations in the zebrafish <em>moonshine (mon)</em> gene specifically disrupt both embryonic and adult hematopoiesis, resulting in severe red blood cell aplasia. We report that <em>mon</em> encodes the zebrafish ortholog of mammalian transcriptional intermediary factor 1γ (TIF1γ) (or TRIM33), a member of the TIF1 family of coactivators and corepressors. During development, hematopoietic progenitor cells in <em>mon</em> mutants fail to express normal levels of hematopoietic transcription factors, including <em>gata1,</em> and undergo apoptosis. Three different <em>mon</em> mutant alleles each encode premature stop codons, and enforced expression of wild-type <em>tif1γ</em> mRNA rescues embryonic hematopoiesis in homozygous <em>mon</em> mutants. Surprisingly, a high level of zygotic <em>tif1γ</em> mRNA expression delineates ventral mesoderm during hematopoietic stem cell and progenitor formation prior to <em>gata1</em> expression. Transplantation studies reveal that <em>tif1γ</em> functions in a cell-autonomous manner during the differentiation of erythroid precursors. Studies in murine erythroid cell lines demonstrate that Tif1γ protein is localized within novel nuclear foci, and expression decreases during erythroid cell maturation. Our results establish a major role for this transcriptional intermediary factor in the differentiation of hematopoietic cells in vertebrates.</p>